The present invention relates to novel 2-substituted adenosine derivatives and pharmaceutical compositions for circulatory diseases comprising the same as an active ingredient.
It has been known that adenosine has potent hypotensive and platelet aggregation inhibitory effects. However, these advantageous effects cannot last for a long period of time. In addition, adenosine gives rise to some undesirable side effects such as a suppressive effect on the heart (a heart-rate reducing effect, etc.) and a central inhibitory effect. It is therefore necessary to solve these problems in order to use adenosine or its derivatives as therapeutic agents for diseases such as hypertension and stenocardia.
To solve the above problems, various 2-substituted adenosine derivatives have been synthesized as described in Chem. Pharm. Bull., 23(4), 759-774 (1975) and Japanese Laid-Open Patent Publication No. 265100/1989. However, even these derivatives cannot provide a satisfactory solution of the above problems, so that they are not practically used as pharmaceuticals as yet.
We have succeeded in synthesis of adenosine derivatives having a specific alkynyl group at the 2 position thereof as reported, for instance, in Chem. Pharm. Bull., 33(4), 1766-1769 (1985), and found that among these derivatives, those compounds having a linear carbon chain as the alkynyl group exhibit a remarkable and lasting vasodepressor activity but have a less adverse effect on the heart rate (see Nucleic Acids Research, Symposium Series No. 16, 97-100 (1985), and Japanese Patent Publications Nos. 33477/1989 and 17526/1990).
The 2-alkynyladenosines having a linear carbon chain have potent and lasting pharmacological effects on circulatory organs and yet entail less serious side effects as compared with other conventional adenosine derivatives. However, there has long been awaited the advent of a compound which is improved in the above advantageous properties, characteristic of the 2-alkynyladenosines.
In recent years, it is reported that a vasodepressor activity, a platelet aggregation inhibitory effect and the like are manifested through A.sub.2 adenosine receptors (hereinafter referred to simply as "A.sub.2 receptor"), while a suppressive effect on the heart, a central inhibitory effect and the like are manifested through A.sub.1 adenosine receptors (hereinafter referred to Simply as "A.sub.1 receptor"). For instance, 5'-N-ethylcarboxamideadenosine (NECA) described in Archs. Pharmacodyn., 230, 140-149 (1977) has been known as a compound having a high affinity for A.sub.2 receptors and is already employed as a ligand for binding assay (see Mol. Pharmacol., 29, 331-346 (1986)). However, this compound also has a high affinity for A.sub.1 receptors so that it tends to give rise to the aforementioned side effects. For this reason, the compound is not utilizable as a therapeutic agent.
Accordingly, adenosine derivatives which have a high affinity for A.sub.2 receptors but a low affinity for A.sub.1 receptors may be useful as therapeutic or prophylactic agents for circulatory diseases, such as hypertension and ischemic heart or brain diseases.
An object of the present invention is therefore to provide 2-substituted adenosine derivatives which have potent and lasting pharmacological activities such as a vasodepressor activity, coronary vasodilating effect, peripheral vasodilating effect, cerebral circulation ameliorating effect, peripheral circulation ameliorating effect, platelet aggregation inhibitory effect and antiarteriosclerotic effect, have high selectivity for A.sub.2 receptors, and yet entail substantially no side effects such as a suppressive effect on the heart and a central inhibitory effect.